1. Field of the Invention
This invention relates to N-(5-tetrazolyl)-pyrimido[1,2-a]quinoline-2-carboxamides and derivatives thereof and to their use as antiallergy agents. More particularly, it relates to N-tetrazolyl-1-oxo-1H-6-(R.sub.3 -substituted)-pyrimido[1,2-a]quinoline-2-carboxamides wherein the 6-substituent is chloro, bromo or lower alkoxy; pharmaceutically-acceptable cationic salts thereof; and derivatives of such compounds wherein the benzenoid ring bears one or more substituents, which are useful as agents for the treatment of allergic reactions, and especially of allergic bronchial asthma; and intermediates therefor.
2. Description of the Prior Art
Allergic reactions, the symptoms resulting from an antigen-antibody interaction, manifest themselves in a wide variety of ways and in different organs and tissues. Common allergic disorders, for example, are allergic rhinitis, a condition characterized by seasonal or perennial sneezing, running nose, nasal congestion, with itching a congestion of eyes; hay fever, a variety of allergic rhinitis that results from hypersensitivity to grass pollens; and bronchial asthma, one of the most disabling and debilitating of allergic reactions, a disease characterized by hyper-reactivity of the bronchi on exposure to various immunogenic or nonimmunogenic stimuli, resulting in bronchospasms with wheezing, short-lived paroxysms and widespread constriction of airway passages. The mechanical obstruction to airflow in airways is generally reversed by the use of bronchodilators, which provide symptomatic relief. In contrast, antiallergy agents prevent the release of mediators of anaphylaxis from tissue stores, thereby acting in a prophylactic manner to preclude elicitation of bronchoconstriction by the mediators.
Efforts to discover medicinal agents to alleviate the symptoms of the abnormal physiologic state have been extensive. As early as 1910, Matthews, Brit. Med. J., 1, 441 (1910) reported the bronchodilator effects of epinephrine. Since then, Chen and Schmidt, J. Pharmacol. Exper. Therap., 24, 339 (1924) reported the use of the alkaloid ephedrine as an orally efficacious bronchodilator with the same spectrum of activity as epinephrine. In 1940, Konzett, Arch. Exp. Path. Pharmak., 197 27 (1940) outlined the effects of the potent aerosol bronchodilator isoproterenol. Cullum et al., Brit. J. Pharmacol. Exp., 35, 141 (1969) reported the pharmacology of salbutamol, a potent bronchodilator of prolonged duration, and active via both oral and aerosol administration. Many bronchodilator preparations contain theophylline. These are generally less potent that the sympathomimetic amines such as isoproterenol and salbutamol, and are ineffective in aerosol administration.
Recently, Cox and co-workers, Adv. in Drug Res., 5, 115 (1970), described the pharmacology of one such agent, disodium cromoglycate [1,3-bis(2-carboxycromon-5-yloxy)-2-hydroxypropane, Intal]. It is not a bronchodilator, but mediates its therapeutic effects by a unique mechanism of action involving inhibition of release of mediators of anaphylaxis and is administered prophylactically. It suffers from lack of oral efficacy and, for optimum results, is administered by inhalation as a solid inhalant. Further, although it is effective against anaphylaxis due to immunoglubulin E (IgE), it is effective against anaphylaxis due to immunoglubulin G (IgG) only at high doses (60-70% protection at 100 and 300 mg./kg.).
Although the aforementioned agents represent outstanding contributions toward the treatment of asthma, many of them exert the undesired side effect of cardiac stimulation.
The synthesis of a 1H-pyrimido[1,2-a]quinoline appears to have first been reported by Antaki et al., J. Chem. Soc., pages 551-555 (1951), who condensed 2-chloroquinoline with ethyl .beta.-amino crotonate in the presence of anhydrous potassium carbonate and a trace of copper bronze to produce 1-oxo-1H-3-methylpyrimido[1,2-a]quinoline. No utility for the compound was reported.
Antaki, J. Am. Chem. Soc., 80, 3066-9 (1958) reports the condensation of 2-aminoquinoline and ethylethoxymethylenecyanoacetate to give ethyl 2-quinolylaminomethylenecyanoacetate which when distilled under reduced pressure afforded 1-oxo-1H-pyrimido[1,2-a]quinoline-2-carbonitrile. The compound demonstrated antischistosomal action.
Richardson, et al., J. Med. Chem., 15, 1203-6 (1972) describe ethyl 1-oxo-1H-pyrimido]1,2-a]quinoline-2-carboxylate and report it to be inactive as an antimicrobial agent. When tested for antiallergy activity by the PCA test it was found to exhibit 100% inhibition at 3 mg./kg. by the intravenous (I.V.) route of administration but is without activity at 1 mg./kg. I.V. Approximately 90% inhibition is demonstrated at 30 mg./kg. by the oral route of administration, but oral activity is absent at a dosage level of 10 mg./kg. via the oral route.